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Ronald V Maier

Publications and source records attributed to Ronald V Maier.

At least 19 recordsLinked to original sources
PubMed2015

Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock.

INTRODUCTION: We wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock. METHODS: We performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients. RESULTS: We found that there was no difference in injury severity between the aged (age &#x2265;55, n&#x2009;=&#x2009;533) and young (age <55, n&#x2009;=&#x2009;1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients' plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states. CONCLUSIONS: We concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

Adult↗
PubMed2014

A better understanding of why murine models of trauma do not recapitulate the human syndrome.

OBJECTIVE: Genomic analyses from blood leukocytes have concluded that mouse injury poorly reflects human trauma at the leukocyte transcriptome. Concerns have focused on the modest severity of murine injury models, differences in murine compared with human age, dissimilar circulating leukocyte populations between species, and whether similar signaling pathways are involved. We sought to examine whether the transcriptomic response to severe trauma in mice could be explained by these extrinsic factors, by utilizing an increasing severity of murine trauma and shock in young and aged mice over time, and by examining the response in isolated neutrophil populations. DESIGN: Preclinical controlled in vivo laboratory study and retrospective cohort study. SETTING: Laboratory of Inflammation Biology and Surgical Science and multi-institution level 1 trauma centers. SUBJECTS: Six- to 10-week-old and 20- to 24-month-old C57BL/6 (B6) mice and two cohorts of 167 and 244 severely traumatized (Injury Severity Score > 15) adult (> 18 yr) patients. INTERVENTIONS: Mice underwent one of two severity polytrauma models of injury. Total blood leukocyte and neutrophil samples were collected. MEASUREMENTS AND MAIN RESULTS: Fold expression changes in leukocyte and neutrophil genome-wide expression analyses between healthy and injured mice (p < 0.001) were compared with human total and enriched blood leukocyte expression analyses of severe trauma patients at 0.5, 1, 4, 7, 14, and 28 days after injury (Glue Grant trauma-related database). We found that increasing the severity of the murine trauma model only modestly improved the correlation in the transcriptomic response with humans, whereas the age of the mice did not. In addition, the genome-wide response to blood neutrophils (rather than total WBC) was also not well correlated between humans and mice. However, the expression of many individual gene families was much more strongly correlated after injury in mice and humans. CONCLUSIONS: Although overall transcriptomic association remained weak even after adjusting for the severity of injury, age of the animals, timing, and individual leukocyte populations, there were individual signaling pathways and ontogenies that were strongly correlated between mice and humans. These genes are involved in early inflammation and innate/adaptive immunity.

Adult↗
PubMed2007

Prehospital care of the injured: what's new.

Emergency medical services (EMS) play a critical role in the trauma system as the point of initial patient care and stabilization and in determining the regional flow of patients and the commitment of resources to the critically injured. Trauma surgeons and emergency physicians need to be involved in the organizational planning of EMS systems to ensure that uniform patient care protocols are developed for triage and treatment. Ongoing efforts should focus on addressing national variability in care provided after injury to ensure optimal outcome for patients in all regions. Through additional research, the best practice and optimal EMS system design will continue to be defined.

Brain Injuries↗
PubMed2007

Vitamin E inhibits endotoxin-mediated transport of phosphatases to lipid rafts.

The production and release of inflammatory mediators is regulated by the coordinated activity of kinases and phosphatases. These proteins are known to regulate one another through an unknown mechanism. Previously, we have demonstrated that autocrine release of oxidants regulates macrophage activation in a similar fashion. The purpose of this study is to determine if attenuated oxidant activity by antioxidant exposure can regulate endotoxin-mediated kinase and phosphatase activity. Human promonocytic THP-1 cells were stimulated with lipopolysaccharide. Selected cells were pretreated with alpha-tocopherol succinate, LY294002, or an AKT inhibitor (1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate). Lipid raft and cellular protein were analyzed for lipid raft toll-like receptor 4 (TLR4) receptor formation and mitogen-activated protein kinase (MAPK) activation. Harvested supernatants were analyzed for tumor necrosis factor (TNF)-alpha production. Lipopolysaccharide stimulation led to the lipid raft mobilization of TLR4 and heat shock protein 70. This was followed by lipid raft mobilization of SH related complex homology 2 domain-containing inositol-5-phosphate (SHIP), activation of the MAPK, and production of TNF-alpha. Pretreatment with alpha-tocopherol succinate did not affect mobilization of TLR4 or heat shock protein 70, but did result in attenuated mobilization of SHIP, activation of the MAPK, and production of TNF-alpha. In addition, alpha-tocopherol succinate was associated with increased activation of the counter-regulatory kinase protein kinase B. Pretreatment with LY294002 or 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate reversed the effects of alpha-tocopherol succinate. Thus, it seems that endotoxin-mediated activation requires the coordinated activity of kinases and phosphatases. Antioxidant exposure in the form of vitamin E seems to attenuate endotoxin-mediated SHIP activation resulting in increased AKT activity, and attenuated MAPK activation and TNF-alpha production.

Cell Differentiation↗
PubMed2006

Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways.

Monitoring genome-wide, cell-specific responses to human disease, although challenging, holds great promise for the future of medicine. Patients with injuries severe enough to develop multiple organ dysfunction syndrome have multiple immune derangements, including T cell apoptosis and anergy combined with depressed monocyte antigen presentation. Genome-wide expression analysis of highly enriched circulating leukocyte subpopulations, combined with cell-specific pathway analyses, offers an opportunity to discover leukocyte regulatory networks in critically injured patients. Severe injury induced significant changes in T cell (5,693 genes), monocyte (2,801 genes), and total leukocyte (3,437 genes) transcriptomes, with only 911 of these genes common to all three cell populations (12%). T cell-specific pathway analyses identified increased gene expression of several inhibitory receptors (PD-1, CD152, NRP-1, and Lag3) and concomitant decreases in stimulatory receptors (CD28, CD4, and IL-2Ralpha). Functional analysis of T cells and monocytes confirmed reduced T cell proliferation and increased cell surface expression of negative signaling receptors paired with decreased monocyte costimulation ligands. Thus, genome-wide expression from highly enriched cell populations combined with knowledge-based pathway analyses leads to the identification of regulatory networks differentially expressed in injured patients. Importantly, application of cell separation, genome-wide expression, and cell-specific pathway analyses can be used to discover pathway alterations in human disease.

Gene Expression Profiling↗
PubMed2006

Endotoxin tolerance attenuates LPS-induced TLR4 mobilization to lipid rafts: a condition reversed by PKC activation.

Endotoxin tolerance is characterized by attenuated macrophage activation to subsequent LPS challenge and can be reversed through nonspecific protein kinase C (PKC) activation, and activation by LPS within naïve cells requires the activation of the cell surface receptors CD14 and TLR4 on lipid rafts. The effect of PKC activation and endotoxin tolerance on lipid raft receptor complex assembly is unknown and the focus of this study. Tolerance was induced in THP-1 cells through LPS pre-exposure. Naïve and tolerant cells were stimulated with LPS, with or without PMA pretreatment to activate PKC. TLR4 surface expression and LPS binding were determined by flow cytometry and immunohistochemistry. Cellular and lipid raft protein was analyzed for the presence and activation of the TLR4 complex components. Harvested supernatants were examined for TNF-alpha production. Total TLR4 surface expression and LPS binding were not affected by tolerance induction. LPS stimulation of naïve cells resulted in TLR4 and heat shock protein (HSP)70 lipid raft mobilization, MAPK activation, and TNF-alpha production. LPS stimulation of tolerant cells was associated with attenuation of all of these cellular events. Although PKC activation by PMA had no effect on naïve cells, it did result in reversal in tolerance-induced suppression of TLR4 and HSP70 lipid raft mobilization, MAPK activation, and TNF-alpha production. In addition, the effects associated with PMA were reversed with exposure to a myristoylated PKC-zeta pseudosubstrate. Thus, endotoxin tolerance appears to be induced through attenuated TLR4 formation following LPS stimulation. This complex formation appears to be PKC-dependent, and restoration of PKC activity reverses tolerance.

Cell Line↗
PubMed2006

Outcomes after ruptured abdominal aortic aneurysms: the "halo effect" of trauma center designation.

BACKGROUND: Trauma centers have an array of services available around the clock that help reduce mortality in injured patients. Having such services available can benefit patients other than those who are injured. We set out to determine whether patients hospitalized with ruptured abdominal aortic aneurysms experience lower morbidity and mortality at regional trauma centers than at other acute care hospitals. STUDY DESIGN: We conducted a retrospective cohort study with the exposure being care at a trauma center and outcomes either mortality or organ failure. We evaluated all patients 40 to 84 years of age with a diagnosis of a ruptured abdominal aortic aneurysm who underwent operation during 2001 in 20 US states with organized systems of trauma care. We determined the relative risk of either death or organ failure at regional trauma centers compared with nondesignated centers. RESULTS: Of 2,450 patients hospitalized for ruptured abdominal aortic aneurysm, 867 (35%) hospitalizations occurred at regional trauma centers. At trauma centers, 41.4% of patients died before hospital discharge, compared with 45.2% of patients at nondesignated hospitals (odds ratio [OR], 0.85; 95% CI, 0.71-1.02). After adjusting for payor, hospital beds, annual hospital admissions, annual inpatient operations, affiliation with a vascular surgery fellowship, and comorbid illnesses, the likelihood of death or organ failure was lower at trauma centers (OR, 0.72; 95% CI, 0.55-0.93). CONCLUSIONS: Care at regional trauma centers after operative repair of ruptured abdominal aortic aneurysm is associated with improved outcomes. We postulate that these benefits reflect the ability of both vascular and general surgeons to immediately mobilize resources for care of the patient requiring urgent operative intervention. The beneficial effects of trauma center designation might extend beyond caring for the critically injured.

Adult↗
PubMed2006

Phosphatidylcholine-specific phospholipase C (PC-PLC) is required for LPS-mediated macrophage activation through CD14.

Lipid rafts, composed of sphingolipids, are critical to Toll-like receptor 4 (TLR4) assembly during lipopolysaccharide (LPS) exposure, as a result of protein kinase C (PKC)-zeta activation. However, the mechanism responsible for this remains unknown. The purpose of this study is to determine if LPS-induced TLR4 assembly and activation are dependent on the sphingolipid metabolite ceramide produced by phosphatidylcholine-specific phospholipase C (PC-PLC) or CD14. To study this, THP-1 cells were stimulated with LPS. Selected cells were pretreated with the PC-PLC inhibitor D609, exogenous C2 ceramide, CD14 neutralizing antibody, or TLR4 neutralizing antibody. LPS led to production of ceramide, phosphorylation of PKC-zeta, and assembly of the TLR4 within lipid rafts. This was followed by activation of the mitogen-activated protein kinase family and the liberation of cytokines. Pretreatment with D609 or CD14 blockade was associated with attenuated LPS-induced ceramide production, TLR4 assembly on lipid rafts, and cytokine production. Pretreatment with TLR4 blockade did not affect LPS-induced ceramide production but was associated with significant attenuation in cytokine production. Treatment with C2 ceramide prior to LPS reversed the inhibitory effects induced by D609 but not of CD14 or TLR4 blockade. C2 ceramide alone induced the activation of PKC-zeta and the assembly of TLR4 but was not associated with cytokine liberation. This study demonstrates that TLR4 assembly and activation following LPS exposure require the production of ceramide by PC-PLC, which appears to be CD14-dependent.

Bridged-Ring Compounds↗
PubMed2006

High dynamic range characterization of the trauma patient plasma proteome.

Although human plasma represents an attractive sample for disease biomarker discovery, the extreme complexity and large dynamic range in protein concentrations present significant challenges for characterization, candidate biomarker discovery, and validation. Herein we describe a strategy that combines immunoaffinity subtraction and subsequent chemical fractionation based on cysteinyl peptide and N-glycopeptide captures with two-dimensional LC-MS/MS to increase the dynamic range of analysis for plasma. Application of this "divide-and-conquer" strategy to trauma patient plasma significantly improved the overall dynamic range of detection and resulted in confident identification of 22,267 unique peptides from four different peptide populations (cysteinyl peptides, non-cysteinyl peptides, N-glycopeptides, and non-glycopeptides) that covered 3,654 different proteins with 1,494 proteins identified by multiple peptides. Numerous low abundance proteins were identified, exemplified by 78 "classic" cytokines and cytokine receptors and by 136 human cell differentiation molecules. Additionally a total of 2,910 different N-glycopeptides that correspond to 662 N-glycoproteins and 1,553 N-glycosylation sites were identified. A panel of the proteins identified in this study is known to be involved in inflammation and immune responses. This study established an extensive reference protein database for trauma patients that provides a foundation for future high throughput quantitative plasma proteomic studies designed to elucidate the mechanisms that underlie systemic inflammatory responses.

Blood Proteins↗
PubMed2006

Variations in rates of tracheostomy in the critically ill trauma patient.

OBJECTIVE: The utility of tracheostomy to expedite weaning and prevent complications in patients with acute respiratory failure is actively debated, with many physicians holding strong opinions regarding the value and timing of this intervention. We postulated that these opinions would be reflected in significant variation in tracheostomy rates across centers. Thus, we set out explore the extent and potential sources of this variation among injured patients cared for in trauma centers in the United States. DESIGN: This is a retrospective cohort study. We used stratification and hierarchical multivariate analysis to evaluate the effect of patient and institutional characteristics on tracheostomy rates and variance decomposition to determine the proportion of variance across institutions explained by patient characteristics. SETTING: Intensive care units within trauma centers participating in the National Trauma Databank. PATIENTS: Injured patients admitted over the years 2001-2003, age >/=16 yrs, with an Injury Severity Score >/=9 and a diagnosis of acute respiratory failure, excluding patients with burn injuries and those with a severe injury to the face or neck who might require tracheostomy for maintenance of an airway. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 17,523 patients meeting inclusion criteria: 4,146 (24%) underwent tracheostomy. The mean tracheostomy rate across centers was 19.6 per 100 hospital admissions with a range of 0-59. This variation persisted after stratification by age, injury mechanism, and severity. Although several patient and injury characteristics were predictive of tracheostomy, there were no identifiable institutional characteristics associated with tracheostomy. Patient characteristics accounted for only 14% of the variance across centers. CONCLUSIONS: There is significant unexplained variation in the rates of tracheostomy in critically injured patients with acute respiratory failure. This variation might reflect preconceived notions of efficacy among physicians practicing in the absence of evidence to guide care. The variation provides evidence of equipoise and emphasizes the need for a well-conducted randomized controlled trial to evaluate the utility of this procedure.

Acute Disease↗
PubMed2006

Patterns of errors contributing to trauma mortality: lessons learned from 2,594 deaths.

OBJECTIVE: To identify patterns of errors contributing to inpatient trauma deaths. METHODS: All inpatient trauma deaths at a high-volume level I trauma center from 1996 to 2004 inclusive were audited. Data were collected with daily trauma registry chart abstraction, weekly morbidity and mortality reports, hospital quality assurance reports, and annual trauma registry analyses of risk of death using TRISS and HARM methodology. Deaths that met criteria for low to medium probability of mortality or those with quality of care concerns were analyzed for errors and then subjected to 3-stage peer review at weekly departmental, monthly hospital, and annual regional forums. Patterns of errors were constructed from the compiled longitudinal data. RESULTS: In 9 years, there were 44,401 trauma patient admissions and 2,594 deaths (5.8%), of which 601 met low to medium mortality risks. Sixty-four patients (0.14% admissions, 2.47% deaths) had recognized errors in care that contributed to their death. Important error patterns included: failure to successfully intubate, secure or protect an airway (16%), delayed operative or angiographic control of acute abdominal/pelvic hemorrhage (16%), delayed intervention for ongoing intrathoracic hemorrhage (9%), inadequate DVT or gastrointestinal prophylaxis (9%), lengthy initial operative procedures rather than damage control surgery in unstable patients (8%), over-resuscitation with fluids (5%), and complications of feeding tubes (5%). Resulting data-directed institutional and regional trauma system policy changes have demonstrably reduced the incidence of associated error-related deaths. CONCLUSIONS: Preventable deaths will occur even in mature trauma systems. This review has identified error patterns that are likely common in all trauma systems, and for which policy interventions can be effectively targeted.

Female↗
PubMed2006

The impact of an intensivist-model ICU on trauma-related mortality.

OBJECTIVE: To evaluate the effect of an intensivist-model of critical care delivery on the risk of death following injury. SUMMARY BACKGROUND DATA: An intensivist-model of ICU care is associated with improved outcomes and less resource utilization in mixed medical and surgical ICUs. The process of trauma center verification assures a relatively high standard of care and quality assurance; thus, it is unclear what the effect of a specific model of ICU care delivery might have on trauma-related mortality. METHODS: Using data from a large multicenter (68 centers) prospective cohort study, we evaluated the relationship between the model of ICU care (open vs. intensivist-model) and in-hospital mortality following severe injury. An intensivist-model was defined as an ICU where critically ill trauma patients were either on a distinct ICU service (led by an intensivist) or were comanaged with an intensivist (a physician board-certified in critical care). RESULTS: After adjusting for differences in baseline characteristics, the relative risk of death in intensivist-model ICUs was 0.78 (0.58-1.04) compared with an open ICU model. The effect was greatest in the elderly [RR, 0.55 (0.39-0.77)], in units led by surgical intensivists [RR, 0.67 (0.50-0.90)], and in designated trauma centers 0.64 (0.46-0.88). CONCLUSIONS: Care in an intensivist-model ICU is associated with a large reduction in in-hospital mortality following trauma, particularly in elderly patients who might have limited physiologic reserve and extensive comorbidity. That the effect is greatest in trauma centers and in units led by surgical intensivists suggests the importance of content expertise in the care of the critically injured. Injured patients are best cared for using an intensivist-model of dedicated critical care delivery, a criterion that should be considered in the verification of trauma centers.

Aged↗
PubMed2006

The delivery of critical care services in US trauma centers: is the standard being met?

BACKGROUND: Although there is substantial evidence supporting the benefits of an intensivist model of critical care delivery, the extent to which this model has been adopted by trauma centers across the United States is unknown. We set out to evaluate how critical care is delivered in Level I and II trauma centers and the extent to which these centers implement evidence-based patient care practices known to improve outcome. METHODS: All Level I and Level II trauma centers in the United States were surveyed using a previously validated questionnaire pertaining to the organizational characteristics of critical care units. Questions identifying the impediments to the implementation of an intensivist model of critical care delivery were added to the original survey. An intensivist model intensive care unit (ICU) was defined as one meeting all of the following criteria: a) the physician director was board certified in critical care; b) >50% of physicians responsible for care were board certified in critical care; c) an intensivist made daily rounds on the patients; and d) an intensive care team had the authority to write orders on the patients. The survey respondents were also queried regarding the extent to which they complied with evidence-based guidelines for care in the ICU. RESULTS: The overall response rate was 65% (295 centers). Only 61% of Level I centers and 22% of Level II centers provided an intensivist model of critical care delivery. Sixty-nine percent of centers had a form of collaborative care with an intensivist, but few centers had dedicated intensivists without responsibilities outside the ICU. The most common reason cited for not involving an intensivist in the delivery of critical care services was a concern regarding a loss of continuity of care. There was limited implementation of evidence-based practices in the ICU; the model of critical care delivery had no effect on rates of implementation of these practices. CONCLUSION: The process of trauma center verification and designation should assure a high quality of trauma care. In keeping with these expectations of quality, the delivery of critical care services in trauma centers should evolve to a model that both includes the trauma surgeon in the care of the injured and allows for collaboration with a dedicated intensivist, who may or may not be a surgeon. The benefits of an intensivist model might be distinct from the utilization of evidence-based practices, suggesting that there might be incremental benefit in using these practices as markers of quality.

Critical Care↗
PubMed2006

Inclusive trauma systems: do they improve triage or outcomes of the severely injured?

BACKGROUND: Trauma systems decrease injury-related mortality, but not all systems have the same configuration. In some systems, nearly all acute care hospitals participate to the extent that their resources allow (inclusive systems), whereas in others, relatively few high-level centers participate (exclusive systems). We postulate that inclusive systems assure that severely injured patients are more likely to be triaged to a level I or II regional trauma center, and this greater degree of participation would lead to lower mortality. METHODS: We used administrative discharge data for 2001 in 24 states with formal systems, and we included all urgently hospitalized adults with an Injury Severity Score>or=16. We categorized states by trauma system configuration ("exclusive", "more inclusive", "most inclusive") based on the proportion of all hospitals designated as a Level I through V trauma center (0-13%, 14-37%, 38-100%, respectively). We compared the rates of triage to a regional trauma center and inpatient death in inclusive states relative to exclusive states, while adjusting for patient- and state-level factors. RESULTS: Out of 61,496 patients, 40,706 (66.2%) were hospitalized at regional trauma centers. Inpatient mortality was 14.7%. After adjusting for patient age, primary payer status, and system maturity, the odds of triage to a regional trauma center were similar in inclusive and exclusive systems. After adjusting for primary payer status, mechanism of injury, and system maturity, the odds of death were similar in more inclusive and exclusive systems (odds ratio, 0.93; 95% confidence interval, 0.80-1.08) but were significantly lower in the most inclusive systems (odds ratio, 0.77; 95% confidence interval, 0.60-0.99). CONCLUSIONS: Severely injured trauma patients have greater inpatient survival in inclusive trauma systems even though they are no more likely to be hospitalized at a regional trauma center. Consideration should be given to continuing implementation of systems with an inclusive configuration, especially in light of other theoretical benefits of these systems, such as better dispersing of trauma care resources in the event of natural disasters or terrorist events.

Adult↗
PubMed2006

Do trauma centers have the capacity to respond to disasters?

BACKGROUND: Concern has been raised about the capacity of trauma centers to absorb large numbers of additional patients from mass casualty events. Our objective was to examine the capacity of current centers to handle an increased load from a mass casualty disaster. METHODS: This was a cross-sectional study of Level I and II trauma centers. They were contacted by mail and asked to respond to questions about their surge capacity as of July 4, 2005. RESULTS: Data were obtained from 133 centers. On July 4, 2005 there were a median of 77 beds available in Level I and 84 in Level II trauma centers. Fifteen percent of the Level I and 12.2% of the Level II centers had a census at 95% capacity or greater. In the first 6 hours, each Level I center would be able to operate on 38 patients, while each Level II center would be able to operate on 22 patients. Based on available data, there are 10 trauma centers available to an average American within 60 minutes. Given the available bed capacity, a total of 812 beds would be available within a 60-minute transport distance in a mass casualty event. CONCLUSIONS: There is capacity to care for the number of serious non-fatally injured patients resulting from the types of mass casualties recently experienced. If there is a further continued shift of uninsured patients to and fiscally driven closure of trauma centers, the surge capacity could be severely compromised.

Cross-Sectional Studies↗